Novel difluorinated gem compounds, preparation methods thereof and applications of same

ABSTRACT

This invention relates to a mini-type electric vehicle, which is mainly used for individual person or traffic in a certain field. It includes frame, seat, front &amp; rear wheel, driving device, battery, steering system and front wheel suspension device. A casing, where the battery is placed on, protrudes forward at the middle position of the front end of the frame; the suspension device for front wheel appears “Front convex &amp; rear concave” shape and covers the front end of that casing, and pivots to the middle of the front end of the casing. Two front wheels are installed on the front wheel suspension device. The rear edge line of the two front wheels is located at the rear of the battery front edge; Steering system is connected to the front end of the frame and interlocks with the front wheel. Battery is installed at the front so as to balance the weight distribution, improve the driving safety, comfort and steering performance for electric vehicle.

The invention relates to a method for the synthesis of gem-difluorinatedcompounds. More specifically, but not exclusively, it applies to thepreparation of glycoconjugated compounds and C-glycosides notably formaking antitumoral, antiviral, hypoglycemic, anti-inflammatory agents oreven for immunology, cosmetology and the preparation of glycopeptideanalogs of antifreeze molecules.

In recent years, the number of investigations relating to fluorinatedorganic molecules has increased considerably. This enthusiasm isexplained by the recognition of the impact of fluorine in the biologicalactivity of the molecules. Indeed, physiological properties of bioactivecompounds are changed with the introduction of fluorine and biochemistsare eager for new methods for selectively introducing fluorine.

However, the main contributions as regards new important biologicalmolecules have essentially been made in monofluorination andtrifluorination.

The introduction of the difluoromethylene CF₂ group has neverthelessshown significant importance in compounds such as Gemcitabine® (Gemzar,Lilly) and Vinflunine® (Pierre Fabre) which are presently undergoingclinical trials as antitumoral agents (FIG. 1).

This interest for selective fluorination of biological compounds isrelated to the very nature of the fluorine atom: its electronegativity(the most electronegative element), the C-F binding energy (484kJ.mol⁻¹; C-C: 348 kJ.mol⁻¹).

As a replacement for oxygen, the difluoromethylene CF₂ group has provedto be a particularly attractive candidate:

-   -   Electronegativity of oxygen (3.5) is rather close to that of the        CF₂ group (3.3), on the one hand;    -   on the other hand, during preliminary investigations carried out        in 1984 with replacement of oxygen of a phosphate analog in        adenosine diphosphate (ADP) type structures, it was shown that        CF₂ was a tetrahedral equivalent of oxygen by the spatial        arrangement of both fluorines, as illustrated in FIG. 2.

Moreover, as the electronegativities are very close, electronic effectsdue to the replacement are minimized.

Hence, analogs of phosphotyrosine and phosphoserine illustrated in FIG.3 have been recently synthetized.

These compounds are inhibitors of phosphatase enzymes which are involvedin the transduction of intracellular signals.

Moreover, syntheses of glycoconjugated compound analogs are carefullyunder investigation. These are compounds formed by conjugation between asugar and another compound (aglycone) such as an amino acid(glycoprotein, glycopeptide), a lipid (glycolipid), a steroid or atriterpene, an alkaloid, a ketone . . .

Indeed, the latter, with i.a. glycoprotein and glycolipid which areconstituents of cellular membranes, are compounds widely involved inmany biochemical processes such as intercellular recognition or cellgrowth control. For this reason, glycoconjugated compounds are aconsiderable therapeutic wager and find applications as antitumoral orantiviral agents.

Now, these compounds owing to the presence of an osidic bond (a bondinvolving oxygen said to be in an anomeric position) are fragilerelatively to several enzymatic systems including protease enzymes andhydrolase enzymes.

In order to have the components retain their biological properties,replacement of the oxygen of the osidic bond is therefore of interest,so that this bond is no longer degraded by an enzymatic process.

Analogs where oxygen is replaced with CH₂, have been synthetized, but,in spite of an increase in stability and sterical hindrance similar tothat of oxygen, the CH₂ group has not proved to be a good mimic ofbiological properties of the initial compound.

Other classes of compounds where oxygen is replaced with nitrogen orsulphur, and more recently with a difluoromethylene group are beinginvestigated in order to impart increased stability to glycoconjugatedcompounds in a biological medium.

This O/CF₂ transposition seems particularly suitable for mimickingoxygen on the electronic level; both fluorine atoms playing the role ofboth free doublets of oxygen (FIG. 2).

Several teams are investigating access to C-glycosides (compounds whereanomeric oxygen is replaced with a carbon) but no effective methodapplicable to the large range of sugars encountered in glycoconjugatedcompounds (D-glucose, D-galactose, D-galactosamine, D-glucosamine . . .) has been reported to this day.

More specifically, the object of the invention is therefore to remedysuch drawbacks.

For this purpose, it proposes a gem-difluorinated C-glycoside compoundof general formula I:

wherein

R¹ is a group comprising an alkyl chain substituted with at least oneamine, amide, or acid function,

R² is a hydrogen atom H or a free or protected alcohol function,

R³ is notably an H, CH₃, CH₂OH, CH₂-OGP group wherein GP is a protectivegroup such as an alkyl, benzyl (Bn), trimethylsilyl (TMS),tert-butyl-dimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS),acetate (Ac) . . . ,

Y, Y′, Y″ are independent groups

wherein Y, Y′, Y″=H, OR, N₃, NR′R″, SR′″. . .

-   -   with R=H, Bn, Ac, TMS, TBDMS, TBDPS, . . . ,    -   R′, R″=H, alkyl, allyl, Bn, tosylate (Ts), C(═O)-alkyl,        C(═O)-Bn, . . . ,    -   R′″=H, alkyl, Ac.

In addition, this compound of general formula I may be prepared by areaction between a lactone with general formula II:

wherein R³ is notably a H, CH₃, CH₂-OGP wherein GP is a protective groupsuch as an alkyl, benzyl (Bn), trimethylsily (TMS),tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS),acetate (Ac) . . . ,

Y, Y′, Y″ are independent groups

wherein Y, Y′, Y″=H, OR, N₃, NR′R″, SR″′

-   -   with R=H, Bn, Ac, TMS, TBDMS, TBDPS, . . . ,    -   R′, R″=H, alkyl, allyl, Bn, tosylate (Ts), C(=O)-alkyl,        C(=O)-Bn, . . . ,    -   R′″=H, alkyl, Ac.

and at least one halogenated derivative with general formula XCF₂CO₂R⁸,wherein X is a halogen, in the presence of zinc, or of a lanthanidederivative and R⁸=alkyl, aryl . . .

Said lanthanide derivative may for example be samarium diiodide SmI₂.

According to an alternative, said method may use zinc associated withtitanocene.

Deoxygenation for passing from a compound of formula I wherein R²=OH toa compound with formula I wherein R²=H, may for example be eitherachieved by direct or radical reduction or even via acetate, tosylate,xanthate, oxalate derivatives, followed by radical reduction.

According to one alternative embodiment, more specifically, thegem-difluorinated compounds may have general formula III:

wherein R⁵ and R⁶=H or a group either functionalized or not such as afunctionalized carbon chain bearing i.a. an amine, amino acid,aminoester function, a peptide chain, a protein, a carbohydrate, asteroid, or a triterpene, an alkaloid, a lignane, or compounds ofpharmacological interest . . .

According to another alternative, the gem-difluorinated compounds maymore specifically have general formulae IVa and IVb:

wherein R⁵, R⁶, R⁷ and R⁹=H or a group either functionalized or not,such as a functionalized carbon chain bearing i.a. an amine, amino acid,aminoester function, a peptide chain, a protein, a carbohydrate, asteroid, or a triterpene, an alkaloid, a lignane, or compounds ofpharmacological interest.

One of the intermediate compounds obtained for obtaining compound offormula I may be a compound of general formula V including an esterfunction:

wherein R⁴ may be a group such as an alkyl, aryl, allyl group, thisgroup either being functionalized or not.

This ester function —CO₂R⁴ may be saponified in order to obtain the acidof formula VI:

This ester function —CO₂R⁴ may also be reduced to an alcohol function,for example with sodium tetraborohydride (NaBH₄) or lithium aluminiumtetrahydride (LiAlH₄) in order to give C-glycoside compounds of generalformula VII:

These compounds of general formula VII may themselves be oxidized intoaldehydes by different methods such as the methods of Swern, Dess-Martinin order to obtain compounds of general formula VIII:

Compounds VIII are also accessible from esters V via the thioester andreduction.

Compound VIII may be obtained in the hemiacetalic form.

Non-osidic compounds of formula I, wherein R¹═CH₂—OH, may also beoxidized into aldehydes with either of the aforementioned methods.

In addition, according to another alternative, compounds of formula Iwherein R¹═COOH may be used in a Ugi reaction with an amine, an aldehydeand an isonitrile for obtaining compounds of formula III whereinR¹═—C(═O)—NR⁵R⁶.

According to a last alternative embodiment, compounds of general formulaI may be obtained by coupling a sugar derivative with an amine, forexample an amino acid or a peptide.

Finally, the CF₂ group is particularly resistant to biochemicaldegradation processes and it therefore allows synthesis ofnon-hydrolyzable structures.

Compounds of general formulae I-VIII as well as their possiblederivatives and pharmaceutically acceptable mineral or organic acidaddition salts may for example exist as tablets, capsules, dragees, oralsolutions or suspensions, emulsions, suppositories. In addition topharmaceutically acceptable and non-toxic, inert excipients such asdistilled water, glucose, starch lactose, talc, vegetable oils, ethyleneglycol . . . , the thereby obtained compositions may also containpreservatives.

Other active ingredients may be added into these compositions.

The amount of compounds according to the invention and other possibleactive ingredients in such compositions may vary according toapplications, the age, and the weight of the patient.

Examples for preparing the compounds according to the invention will bedescribed hereafter by way of non-limiting examples.

The encountered acronyms are thereby defined:

eq.: equivalent

g: gram

Hz: hertz

mg: milligram

MHz: megahertz

min.: minute

mL: milliliter

mmol: millimole

μmol: micromole

nmol: nanomole

The examples hereafter describe the preparation of gem-difluorinatedglycoconjugated compounds of general formula I:

These compounds may be synthesized with different methods.

In order to reduce the number of steps during the synthesis ofgem-difluorinated glycoconjugated compounds, lactones 1 were used aselectrophilic substances (FIG. 4). Derivatives 2 were obtained from thelactones 1 by attack of ethyl bromodifluoroacetate 3 in the presence ofzinc Zn or samarium diiodide SmI₂.

It should be noted that this method is general and may be applied to allthe classes of differently substituted glucopyranoses (Y, Y′, Y″=OR, N₃,NR′R″, SR″ . . . ), the starting lactones being easily accessible in oneor more steps from commercial products (for example in the glucoseseries, by oxidizing commercial products in one step).

SYNTHESIS OF INTERMEDIATE C-GLYCOSIDE COMPOUNDS 6 AND 7 (FIGS. 5 and 6):

In the example of FIG. 5, 0.82 g of activated zinc (Zn) (0.82 g, 12.5mmol, 7 eq.) is introduced into a two-neck vial of 100 mL topped by acoolant and an inlet valve. The whole is put in vacuo and the zinc isheated with a heat pistol for about 5 min then the vacuum is releasedwith an argon balloon.

15 mL of anhydrous tetrahydrofurane (THF) are added and the obtainedsolution is refluxed. The mixture, prepared under argon and consistingof the lactone 4 (0.960 g, 1.782 mmol, 1 eq.), of ethylbromodifluoroacetate BrCF₂COOEt 5 (0.69 mL, 5.346 mmol, 3 eq.) andanhydrous tetrahydrofurane (15 mL) is introduced therein.

The assembly is left to reflux for 2 h 30 min (the reaction is followedby thin layer chromatography (TLC) with a (3:7) ethylacetate/cyclohexane mixture as an eluent), then 30 mL of hydrochloricacid of concentration 1N and dichloromethane are added to the solution.

The phases are separated and extraction is achieved with dichloromethane(3×10 mL of dichloromethane are successively added to the aqueous phaseand extracted) the organic phases are collected, dried on anhydrousmagnesium sulfate (MgSO₄), filtered and concentrated on the evaporatorin vacuo.

Separation is achieved by chromatography on a silica column with acyclohexane/ethyl acetate mixture as eluent in proportions of nine forone. After concentration of the collected fractions, product 6 exists asa yellowish oil with a 89% yield by weight as a single diastereoisomer.

Compound 6 is obtained as a separable mixture of both diastereoisomers((2:1) mixture) with a 62% yield by weight if samarium diiodide is usedinstead of zinc.

Characteristics of the devices used for performing the analyses of allthe compounds described in the present application are indicated below:

¹H, ¹³C, ¹⁹F NMR spectra were recorded on BRUKER DPX 300 and DPX 600spectrometers. In ¹H and ¹³C NMR, tetramethylsilane is used as aninternal standard. In ¹⁹F-NMR, the external standard isfluorotrichloromethane (CFCl₃). Chemical shifts are expressed in partsper million (ppm), the coupling constants J in Hertz (Hz).

The following abbreviations were used:

s for singlet, b for a broad singlet, d for doublet, t for triplet, qfor quadruplet, m for multiplet or massive, dd for doublet of doublet .. .

Infrared spectra were plotted on a PERKIN-ELMER PARAGON 500 FT-IR devicein liquid film on sodium chloride crystal or in KBr tablet (for solids).The absorption frequencies are expressed in cm⁻¹.

Mass spectra were obtained on a JEOL AX 500 spectrophotometer with a FABJEOL gun (Xe, 4 kV, 10 mA).

Separations by column chromatography were achieved under slight pressureby following the chromatographic techniques on Kieselgel 60 silica(230-400 mesh, Merck).

Follow-up is provided by chromatography on thin layers (TLC) withKieselgel 60F-254-0.25 mm plates. The ratio of the migration distance ofa compound on a given support over the migration distance of an eluentis called the front ratio (Rf).

The analyses performed for confirming the structure of the obtainedproduct 6 are shown below:

Thin layer chromatography (TLC)

Rf=0.55, eluent: ethyl acetate/cyclohexane 3:7

NMR data:

¹⁹F-NMR (282 MHz; solvent: deuterated chloroform (CDCl₃)) −117.67, d,2J_(F). _(F)=256 Hz; −120.03, d, 2 J_(F-F)=256 Hz

¹H-NMR (300 MHz; solvent: deuterated chloroform (CDCl₃)) 1.19, t,³J=7.14 Hz, 3H : CH₃(OEt); 3.52-3.70, m, 3H (H₅+2H₆); 3.90-3.95, m, 3H:H₂+H₃+H₄, 4.18, q, ³J=7.14 Hz, 2H: CH₂(OEt); 4.39-5.19, m, 8H: 4CH₂(OBn); 7.14-7.24, m, 20H: 4×5 CH(Ph).

¹³C-NMR (75.5 MHz; solvent: deuterated chloroform (CDCl₃)): 14.29,CH₃(OEt); 63.89, CH₂(OEt); 68.68, CH₂(C₆); 73.06, CH; 73.82, 75.47,75.67, 76.37: 4xCH₂(OBn); 77.83, CH; 78.62, CH; 83.79, CH; 96.59, dd,²J_(C-F)=28.17 Hz and ²J_(C-F)=26.44 Hz, —CF₂C(OH)O—; 112.79, dd,¹J_(C-F)=263.6 Hz and ¹J_(C-F)=259.6 Hz, CF₂; 137-138 CH(Ph); 163.32,dd, ²J_(C-F)=31.6 Hz and 2J_(C-F)=31.0 Hz, CFCOOEt.

IR (cm⁻¹)

4059.6, 3478.5, 3089.5, 3064.3, 3031.6, 2923.7, 2852.0, 2257.3, 2925.7,1875.4, 1769.3, 1663.6, 1605.9, 1586.4, 1497.3, 1454.0, 1396.7, 1372.1,1315.6, 1087.7, 1027.9, 910.6, 856.8, 802.1, 736.7, 698.1, 648.9, 605.5,540.9, 462.7.

Mass spectrometry: FAB+ (Xe, 4 kV, 3-nitrobenzylalcohol matrix)686(2%)=(M+Na)+, 663(4%)=M+, 661(6%), 572(3%)=(M−Bn)+,554(3%)=(M−Bn−H₂O)+, 463(4%), 391(12%), 307(14%), 289(12%), 271(16%),181(96%), 154(100%), 136(84%), 107(50%), 91(100%), 81(46%), 69(40%),55(76%), 43(64%), 29(20%)

Deoxygenation to have access to derivatives 7 may then be performedthrough different routes (direct or radical reduction, via acetate,tosylate, xanthate derivatives . . . ).

Saponification may be performed quasi-quantitatively under differentconditions whether with sodium, potassium or lithium hydroxides in anaqueous ethanol or THF solution (FIG. 6):

In a flask containing the ester 6 (0.5 g, 1.75 mmol 1 eq.) intetrahydrofurane: (5 mL) or in ethanol (5 mL), an aqueous solution oflithine LiOH (2M, 0.75 mL, 2 eq.) or an aqueous caustic soda solutionNaOH (0.07 g, 1.6 mmol) is added, then stirring is continued for twelvehours. The medium is evaporated when ethanol is used, then taken up withdichloromethane. The mixture is acidified with hydrochloric acid HCl 1M,then extracted several times with dichloromethane. The organic phasesare collected, dried on MgSO₄, filtered and concentrated.

The obtained product is a colorless oil and the yield is quantitative.

NMR data:

¹⁹F-NMR (CDCl₃, 282.5 MHz)

−117.4, d (²J_(F-F)=258 Hz); −119.1, d (²J_(F-F)=258 Hz).

¹H-NMR (CDCl₃, 300 MHz):

3.40-3.60, m, 3H, H5 and H6; 3.90-4.00, m, 3H, H2, H3 and H4; 4.38-4.79,m,

8 H, 4 CH₂(OBn); 7.05-7.22, m, 20 H, H ar.

¹³C-NMR (CDCl₃, 75.5 MHz)

68.6 (C6); 72.2 (C5); 73.5, 75.5, 75.9, 76.4 (4 CH₂(OBn)); 77.7, 78.5,83.6 (C2; C3 and C4); 96.0, dd, ²J_(C-F)=27.0 Hz and ²J_(C-F)=28.7 Hz ,—CF₂Cl(OH)O—; 112.4 , dd, ¹J_(C-F)=260.3 Hz and ¹J_(C-F)=259.2 Hz, CF₂128.1, 128.2, 128.4, 128.8, 128.9, 129.0 (ar C.); 137.2, 137.7, 137.9,138.6 (ar. C, quat) 163.6, dd, ²J_(C-F)=30.5 Hz and ²J_(C-F)=32.8 Hz,CF₂COOH.

Synthesis of a Difluorinated Gem-compound From Compounds 6 and 7

Reaction with amines

This reactivity enables access to very interesting compounds, analogs ofglycopeptides.

Derivatives of compound 6 react with different primary or secondaryamines leading to the corresponding amides. The amines used arealiphatic, benzyl or aromatic amines and amino acid derivatives such aslysine (FIG. 7):

In a flask under an inert atmosphere containing the starting product 6(50 mg; 0.075 mmol; 1 eq.) in a solution and Boc-lysine-OMe acetate 8(48 mg; 0.15 mmol; 2 eq.) in dichloroethane DCE (3 ml), triethylamineEt³N (53 μl; 0.375 mmol; 5 eq.) is added. The mixture is refluxed forforty eight hours and then the solvent is evaporated.

Purification of the crude product is achieved by chromatography on asilica column with a cyclohexane/ethyl acetate mixture as an eluent inproportions of seven for three.

After concentration, product 9 exists as a light yellow solid with a 84%yield by weight.

NMR data:

¹⁹F-NMR (CDCl₃, 282.5 MHz)

−117.4, d, (²J_(F-F)=259 Hz); −121.9, d, (²J_(F-F)=259 Hz).

¹H-NMR (CDCl₃, 300 MHz)

1.18-1.60, m, 15 H, (CH₃)₃C and (CH₂)₃; 3.06-3.19, m, 2 H, CH₂N;3.52-3.69, m, 6 H, H5; H6 and CO₂CH₃; 3.84-4.18, m, 4 H, H2; H3; H4 andCHN; 4.36-4.85, m, 8 H, 4 CH₂Bn; 5.01, d, J=8.3 Hz, 1 H, NHBoc; 6.60, m,1 H, NH; 7.10-7.23, m, 20 H, H ar.

¹³C-NMR (CDCl₃, 75.5 MHz) 22.7, 28.8 ((CH₂)₂); 28.9 ((CH₃)₃C); 32.5(CH₂); 39.6 (CH₂N); 52.7 (CO₂CH₃); 53.6 (CHN); 68.7 (C6); 73.6, 75.3,75.8, 76.4 (4 CH₂Bn); 72.1, 77.9, 78.6, 83.6 (C2, C3, C4 and C5); 96.1,dd, ²J_(C-F)=27.4 Hz (CF₂CO(OH)); 112.5, dd, ¹J_(C-F)=261.7 Hz (CF₂);127.6, 127.7, 127.8, 128.3, 128.4, 128.5 (ar. C) , 137.5, 137.9, 138.0,138.3 (ar. C quat.); 155.6 (CO₂Me); 163.7, dd, ²J_(C-F)=27.4 Hz(CF₂CONH); 173.3 (NHCO₂tBu).

A glycosylated derivative of alanine may be obtained from compound 6(FIG. 8) or from compound 7 (FIG. 9) according to three differentprocedures:

The first procedure A is identical with that used for compound 9 derivedfrom lysine. The weight yield for compound 11 is 30% (FIG. 8).

The second procedure B (FIG. 9) is the following:

BOP (benzotriazol-1-yloxy-tris(dimethylamino)-phosphoniumhexafluorophosphate) (35 mg; 7.87*10⁻³ MMol; 1 eq.) anddiisopropylethylamine DIEA (28 μL; 0.016 mmol; 2 eq.) are introducedinto a flask under an inert atmosphere containing the acid 7 (50 mg;7.87*10⁻³ mmol; 1 eq.) in dichloromethane DCM (2 mL). The reactionmedium is stirred for one hour and then a solution consisting of alanine10 (11 mg; 7.87*10⁻³ mmol; 1 eq.) and DIEA (14 μL; 7.87*10⁻³ mmol; 1eq.) in dichloromethane (2 mL) is added to the reaction. Stirring iscontinued for twenty four hours. The medium is then washed with asolution of hydrochloric acid HCl 1M. The organic phase is dried onmagnesium sulfate, filtered and evaporated.

The crude product is then purified on a preparatory silica plate byusing a cyclohexane/ethyl acetate mixture as eluent in proportions ofseven to three.

Product 11 is obtained as white crystals with a 77% yield by weight.

The third procedure C (FIG. 9) is the following:

In a flask under an inert atmosphere containing the acid 7 (50 mg;7.87*10⁻³ mmol; 1 eq.) in dichloromethane (2 mL), BOPCl(bis-(2-oxo-3-oxazolidinyl)phosphinic chloride) (40 mg; 7.87*10⁻³ mmol;1 eq.) and diisopropylethylamine DIEA (28 μL; 0.016 mmol; 2 eq.) areintroduced. Next stirring is continued for one hour before adding to thereaction a solution consisting of the alanine derivative 10 (22 mg;0.016 mmole; 2 eq.) and diethylamine DIEA (44 μL; 0.023 mmole; 3 eq.) indichloromethane (2 mL). Stirring is continued for twenty four hours thenthe medium is washed with a HCl 1M solution. The organic phase is driedon magnesium sulfate, filtered and evaporated.

The crude product is then purified on a preparatory silica plate byusing a cyclohexane/ethyl acetate mixture as an eluent, in proportionsof seven to three.

Product 11 is obtained as white crystals with a 44% yield by weight.

NMR data:

¹⁹F-NMR (CDCl₃, 282.5 MHz)

−118.0, d, (²J_(F-F)=259 Hz); −122.2, d, (²J_(F-F)=259 Hz).

¹H-NMR (CDCl₃, 300 MHz)

1.26, d, ³J=7.2 Hz, 3 H, CH₃; 3.50-3.66, m, 3 H, H5 and H6; 3.63, S, 3H, CO₂CH₃; 3.89-3.96, m, 3 H, H2, H3 and H4; 4.40-4.81, m, 10 H, NH; CHNand 4 CH₂Bn; 7.11-7.21, m, 20 H, ar. H. ¹³C-NMR (CDCl₃, 75.5 MHz) 16.7(CH₃); 47.2 (CHN); 51.7 (CO₂CH₃); 67.3 (C6); 72.3, 73.9, 74.3, 75.0 (4CH₂Bn); 70.9, 76.2, 77.1, 82.2 (C2, C3, C4 and C5); 126.6-127.4, m (ar.C); 136.5, 136.9, 137.0, 137.4 (ar. C, quat.); 171.0 (CO₂Me).

Coupling reactions with the following amino acids such as phenylalanine,threonine, methionine, proline as well as with a dipeptide were achievedby using BOPCl as coupling agent, i.e., by following the same method asprocedure C upon coupling with alanine (FIG. 10).

Product 112b is obtained as white crystals with a 42% yield by weight(FIG. 11).

NMR data:

¹⁹F-NMR (CDCl₃, 282.5 MHz)

−117.7, d, (²J_(F-F)=261 Hz); −121.6, d, (²J_(F-F)=261 Hz).

¹H-NMR (CDCl₃, 300 MHz)

3.07, m, 2 H, CH₂Ph; 3.44-3.67, m, 3 H, H5 and H6; 3.57, S, 3 H, CO₂CH₃;3.91-3.98, m, 3 H, H2, H3 and H4; 4.25-4.85, m, 10 H, NH, CHN and 4

CH₂Bn; 7.00-7.14, 25 H, ar. H

¹³C-NMR (CDCl₃, 75.5 MHz)

37.5 (CH₂Ph); 52.4 (CO₂CH₃); 53.1 (CHN); 68.3 (C6); 73.2, 75.0, 75.3,76.0 (4 CH₂Bn); 72.0, 77.0, 78.2, 83.2 (C2, C3, C4 and C5); 127.3-129.3,m (ar. C); 135.0, 137.5, 137.9, 138.0, 138.4 (ar. C quat.); 170.3(CO₂Me).

Product 12c is obtained as white crystals with a 28% yield by weight(FIG. 12).

NMR data:

¹⁹F-NMR (CDCl₃, 282.5 MHz)

−118.3, d, (²J_(F-F)=257 Hz); −121.2, d, (²J_(F-F)=257 Hz).

¹H-NMR (CDCl₃, 300 MHz)

1.12, d, ³J=6.4 Hz, 3H, CH₃; 3.48-3.64, m, 3H, H5 and H6; 3.7, s, 3H,CO₂CH₃; 3.89-4.00, m, 3H, H2, H3 and H4; 4.22-4.82, m, 11H, NH; CHN,CHOH and 4 CH₂Bn; 7.0-7.24, m, 20H, ar. H

¹³C-NMR (CDCl₃, 75.5 MHz)

20.5 (CH₃); 53.2 (CO₂CH₃); 57.8 (CHN); 68.6 (CHOH); 68.7 (C6); 73.5,75.4, 75.8, 76.4 (4 CH₂Bn); 72.2, 77.2, 78.4, 83.6 (C2, C3, C4 and C5);128.1-128.9 m (ar. C); 137.8, 137.9, 138.1, 138.7 (ar. C quat.); 170.5(CO₂Me).

Product 12d is obtained with a 36% yield by weight (FIG. 13).

NMR data:

¹⁹F-NMR (CDCl₃, 282.5 MHz)

−117.4, d, (²J_(F-F)=260 Hz), −121.7, d, (²J_(F-F)=260 Hz).

¹H-NMR (CDCl₃, 300 MHz)

1.89-1.99, m, 2H, CH₂; 2.09, s, 3H, SCH₃; 2.46, t, ³J=7.0 Hz, 2H, CH₂S;3.58-3.77, m, 3H, H5 and H6; 3.68, s, 3H, CO₂CH₃; 3.96-4.03, m, 3H, H2,H3 and H4; 4.43-4.88, m, 1OH, NH; CHN and 4 CH₂Bn; 7.14-7.30, m, 20H,ar. H. ¹³C-NMR (CDCl₃, 75.5 MHz)

15.7 (CH₂); 29.9 (SCH₃); 31.6 (CH₂S); 51.8 (CO₂CH₃); 53.2 (CHN); 68.6(C6); 73.6, 75.4, 75.8, 76.4 (4 CH₂Bn); 72.4, 77.4, 78.5, 85.6 (C2, C3,C4 and C5); 128.1-128.9 m (ar. C); 137.9, 138.3, 138.5, 138.8 (ar. Cquat.); 171.5 (CO₂Me).

Product 12e is obtained as white crystals with a 32% yield by weight(FIG. 14).

NMR data:

¹⁹F-NMR (CDCl₃, 282.5 MHz)

−112.6, d, (²J_(F-F)=267 Hz); −113.7, d, (²J_(F-F)=261 Hz); −117.2 d(²J_(F-F)=261 Hz); −117.3, d, (²J_(F-F)=267 Hz).

¹H-NMR (CDCl₃, 300 MHz)

1.52-1.89, m, 4H, (CH₂)₂; 3.5-3.63, m, 3H, H5 and H6; 3.67, s, 3H,CO₂CH₃; 3.82-4.06, m, 5H, CH₂N; H2; H3 and H4; 4.33-4.92, m, 9H, CHN and4 CH₂Bn; 7.10-7.20, m, 20H, ar. H.

Product 12f is obtained as white crystals with a 17% yield by weight(FIG. 15).

NMR data:

¹⁹F-NMR (CDCl₃, 282.5 MHz)

−117.6, d, (²J_(F-F)=257 Hz); −122.4, d, (²J_(F-F)=257 Hz).

¹H-NMR (CDCl₃, 300 MHz)

1.35, d, ³J=7.2 Hz, 3 H, CH₃, 3.05, m, 2 H, CH₂Ph; 3.5-3.71, m, 3H, H5and H6; 3.70, s, 3H, CO₂CH₃; 3.89-4.01, m, 3H, H2; H3 and H4; 4.26-4.89,m, 11H, NH, 2 CHN and 4 CH₂Bn; 6.05, m, 1 H, NH; 7.10-7.20, m, 25H, ar.H

Compound 7 may also be used in a UGI reaction with an amine such asbenzylamine 18, an aldehyde 19 and an isonitrile such as ethylisocyanate 20 for compounds 13-17.

This is a route for accessing the synthesis of therapeutical compounds(manno- and fucopeptides) which are inhibitors of the bond betweenselectine and the tetrasaccharide, sialyl Lewis^(x) (sLe^(x)).

Leucocytes play an important role in many inflammatory and immunologicalphenomena. In many of these phenomena, the first steps are interactionsbetween endothelial cells and leucocytes flowing in the blood.

Investigation of molecules specific to the surface of the cells,involved in these interactions, has shown that leucocytes andendothelial cells have at their surface specific lectins calledselectins. These are cellular adhesion molecules of the family ofcalcium-dependent molecules. sLe^(x) is one of the ligands involved inthe bonding between selectins, thereby causing adhesion of theleucocytes onto the endothelial tissue leading to acute forms ofdiseases such as rheumatismal arthrosis, psoriasis, cancer.

Consequently, development of sLe^(x)-inhibiting small size molecules isan attractive therapeutical approach.

Synthesis of Compound 13 (FIG. 17):

All the reagents are diluted in dry methanol in order to obtain aconcentration of 1M.

In a 25 mL flask, a hexanal solution 0.081 mL; 0.675 mmol) is placedwith a benzylamine solution 18 (0.059 mL; 0.54 mmole) and the mixture isstirred under argon for two hours at room temperature.

Next, a solution of ethyl isocyanoacetate 20 (0.074 mL; 0.675 mmol) anda solution of gem-difluorinated D-glucose as an acid 7 (286 mg; 0.45mmol) are added and the mixture is stirred under argon for twenty fourhours at room temperature.

Methanol is then evaporated and purification of the product is achievedby chromatography on a silica column with a gradient of ethylacetate/cyclohexane as eluent, ranging in proportions from 1:9 to 2:8.

TLC

Rf=0.18, eluent: ethyl acetate/cyclohexane (2:8).

NMR data:

¹⁹F-NMR (CDCl₃)

−104.39 (d, ²J_(F-F)=260.1 Hz); −104.85 (d, ²J_(F-F)=257.9 Hz); −108.61(d, ²J_(F-F)F=255.8 Hz); −108.89 (d, ²J_(F-F)=254.7 Hz); −108.95 (d,²J_(F-F)=260.1 Hz); −112.49 (d, ²J_(F-F)=255.8 Hz); −114.35 (d,²J_(F-F)=254.7 Hz); −116.17 (d, ²J_(F-F)=257.9 Hz). ¹H-NMR (CDCl₃)

0.69, t, 3H, H₂0, ³J_(H19-H20)=6.9 Hz; 0.90-1.10, m, 6H , 1.15, t, 5H,H₁, ³J_(H1-H2)=7.1 Hz; 3.41-3.74, m, 4H; 3.78-3.99, m, 4H; 4.07, q, 2H,H₂, ³J_(H1-H2)=7.1 Hz; 4.36-4.55, m, 4H; 4.61-6.97, m, 8H; 6.76, t,0.7H, H₅, ³J_(H4-H5)=5.5 Hz; 6.82, t, 0.3H, H₅ rotamer, ³J_(H4-H5)=5.3Hz; 7.00-7.26, m, 25H, H_(Ph).

Mass spectrometry: (direct introduction, FAB+):

M+Na=959.6

M+K=975.7

Synthesis of compound 14 (FIG. 18):

All the reagents are diluted in dry methanol in order to obtain aconcentration of 1M.

A solution of trimethylacetaldehyde (0.073 mL; 0.675 mmol) is placed ina 25 mL flask, with a solution of benzylamine 18 (0.059 mL; 0.54 mmol)and the mixture is stirred under argon for two hours at roomtemperature.

Next, a solution of ethyl isocyanoacetate 20 (0.074 mL; 0.675 mmol) anda solution of gem-difluorinated D-glucose as an acid 7 (286 mg; 0.45mmol) are added and the mixture is stirred under argon for twenty fourhours at room temperature.

The methanol is evaporated and purification of the product is achievedby chromatography on a silica column with an ethyl acetate/cyclohexanegradient as eluent, in proportions from 1:9 to 3:7.

The obtained product is a yellow oil in the form of two diastereoisomerswhich are separated.

Analyses of the 1^(st) Diastereoisomer 14a

TLC

Rf=0.70, eluent: ethyl acetate/cyclohexane (4:6).

NMR data:

¹⁹F-NMR (CDCl₃):

−105.31 (d, ²J_(F-F)=267.0 Hz); −106.69 (d, ²J_(F-F)=267.0 Hz).

¹H-NMR (CDCl₃)

0.99, s, 9H, H₁₈; 1.16, t, 3H, H₁, ³J_(H1-H2)=6.9 Hz; 3.39-3.65, m, 4H;3.90, dd, 2H, J=8.9 Hz; 4.00-4.15, q, 3H, H₂, ³J_(H1-H2)=6.9 Hz; 4.37,d, 1 H, J=11.7 Hz; 4.49, t, 2H, J=10.7 Hz; 4.69-4.97, m, 7H; 5.53, s, 1H, H₇; 6.49, m, 1 H, H₅; 7.08-7.27, m, 25H, H_(Ph).

Mass Spectrometry: (Direct Introduction, FAB+):

M+Na=945.4

Analyses of the 2nd Diastereoisomer 14b

TLC

Rf=0.65, eluent: ethyl acetate/cyclohexane (4:6).

NMR data:

¹⁹F-NMR (CDCl₃):

−107.15 (d, ²J_(F-F)=255.7 Hz).

¹H-NMR (CDCl₃)

1.02, s, 9H, H₁₈; 1.16, t, 3H, H₁, ³J_(H1-H2)=7.0 Hz; 3.52-4.00, m, 9H;4.09, q, 2H, H₂, ³J_(H1-H2)=7.0 Hz; 4.33-4.86, m, 8H; 4.97, dd, 2H, H₁₆,H₁₆, ²J_(H16-H16)=17.3 Hz; 5.33, s, 1 H, H7; 6.49, m, 1 H, H₅;6.98-7.27, m, 25H, H_(Ph),.

Mass spectrometry: (MALDI+):

M+Na=945.4

Synthesis of Compound 15 (FIG. 19):

All the reagents are diluted in dry methanol in order to obtain aconcentration of 1M.

A solution of 3,4,5-trimethoxybenzaldehyde 22 (0.132 g; 0.675 mmol) isplaced in a 25 mL flask, with a benzylamine solution 19 (0.059 mL; 0.54mmole) and the mixture is stirred under argon for two hours at roomtemperature.

Next, a solution of ethyl isocyanoacetate 20 (0.074 mL; 0.675 mmol) anda solution of gem-difluorinated D-glucose as an acid 7 (286 mg; 0.45mmol) are added and the mixture is stirred under argon for twenty fourhours at room temperature.

The methanol is evaporated and purification of the product is achievedby chromatography on a silica column with an ethyl acetate/cyclohexanegradient as eluent, ranging in proportions from 1:9 to 3:7.

The obtained product is a yellow oil in the form of two diastereoisomers15a, 15b, which are separated.

Analyses of the 1^(st) diastereoisomer 15a

TLC

Rf=0.41, eluent: ethyl acetate/cyclohexane (4:6).

NMR data:

¹⁹F-NMR (CDCl₃):

−111.63, s.

¹H-NMR (CDCl₃):

1.18, t, 3H, H₁, ³J_(H1-H2)=7.2 Hz; 3.38, t, 1 H, J=6.6 Hz; 3.58, s, 9H,H₁₇ 3.65, s, 4H; 3.93-4.14, m, 7H; 4.40-4.53, m, 3H; 4.70-4.87, m, 3H;4.86, dd, 2H, H₁₆, H₁₆, 2J_(H16-H16′)=16.9 Hz; 5.33, s, 1 H; 6.38, s, 1H, H₇; 6.43, t, 1 H, H₅, ³J_(H4-H5)=4.5 Hz; 6.90-7.25, m, 27H, H_(Ph).

Mass spectrometry: (direct introduction, FAB+):

M+Na=1055.7

Analyses of the 2nd diastereoisomer 15b

TLC

Rf=0.32, eluent: ethyl acetate/cyclohexane (4:6).

NMR data:

¹⁹F-NMR (CDCl₃)

−108.12 (d, ²J_(F-F)=251.9 Hz); −115.19 (d, ²J_(F-F)=251.9 Hz).

¹H-NMR (CDCl₃)

1.17, t, 3H, H₁, ³J_(H1-H2)=7.0 Hz; 3.32-3.41, m, 1 H; 3.65, s, 9H, H₁₇;3.70, s, 3H; 3.78-3.98, m, 5H; 4.08, q, 4H, H₂, ³J_(H1-H2)=7.0 Hz; 4.32,s, 2H; 4.60, dd, 2H, J=10.54 Hz; 4.67, s, 2H; 4.87, s, 1 H; 5.09, s, 1H; 6.30, t, 1 H, H₅, ³J_(H4-H5)=4.9 Hz; 6.52, s, 2H, H₇; 6.86-7.23, m,271, H_(Ph).

Mass spectrometry: (direct introduction, FAB+):

M+Na=1055.7

Synthesis of compound 16 (FIG. 20):

All the reagents are diluted in dry methanol in order to obtain aconcentration of 1M.

A solution of benzaldehyde (0.059 mL; 0.675 mmol) is placed with thesolution of benzylamine 18 (0.059 mL; 0.54 mmol) in a 25 mL flask, andthe mixture is stirred under argon for two hours at room temperature.

Next, a solution of ethyl isocyanoacetate 20 (0.074 mL; 0.675 mmol) anda solution of difluorinated gem-D-glucose as an acid 7 (286 mg; 0.45mmol) are added and the mixture is stirred under argon for twenty fourhours at room temperature.

The methanol is evaporated and the purification of the product isachieved by chromatography on a silica column with an ethylacetate/cyclohexane gradient as eluent ranging in proportions from 1:9to 3:7.

The product is obtained in the form of two diastereomers 16a, 16b, whichare separated.

Analyses of the 1^(st) diastereoisomer 16a

TLC

Rf=0.26, eluent: ethyl acetate/cyclohexane (3:7).

NMR data:

¹⁹F-NMR (CDCl₃):

−111.66, s, 2F.

¹H-NMR (CDCl₃):

1.15, t, 3H, H, ³J_(H1-H2)=7.0 Hz; 3.52-3.79, m, 3H; 3.83, dd, 1 H,J=4.5 Hz; 3.90-4.01, m, 4H, 4.07, q, 2H, H₂, J=7.0 Hz; 4.36-4.52, m, 4H;4.68-4.82, m, 5H; 4.94, dd, 2H, H₁₆, ²J_(H16-H16)=15.8 Hz; 5.20, s, 1 H,H₇; 6.29, t, 1 H, H₅, ³J_(H4-H5)=4.5 Hz; 6.96-7.23, m, 30H, H_(Ph).

¹³C-NMR (CDCl₃): 14.2, C₁; 41.6, C₄; 52.0, 61.6, C₂; 66.2, 68.5, 71.7,73.5, 75.1, 75.4, 75.9, 77.5, 78.6, 83.5, 96.9, t, C₁₀, ²J_(C10-F)=27.6Hz; 114.3, t, C₉, ¹J_(C-F)=262.9 Hz; 126.9, 127.2, 127.7, 127.8, 127.9,128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 128.5, 128.6, 128.8, 130.0,133.0, 136.3, 137.8, 138.0, 128.6, 165.1, t, C₈, ²J_(C8-F)=26.4 Hz;168.3; 169.7.

Mass spectrometry: (MALDI+):

M+Na=965.5

M+K=981.5

Analyses of the 2 diastereoisomer 16b

TLC

Rf=0.71, eluent: ethyl acetate/cyclohexane (5:5).

NMR data:

¹⁹F-NMR (CDCl₃)

−107.71 (d, ²J_(F-F)=253.1 Hz); −115.09 (d, ²J_(F-F)=253.1 Hz).

¹H-NMR (CDCl₃)

1.16, t, 3H, H₁, ³J_(H1-H2)=7.0 Hz, 3.35-3.40, m, 1 H; 3.51-3.70, m, 4H;3.84-4.00, m, 5H; 4.08, q, 2H, H₂, ³J_(H1-H) ₂=7.0 Hz; 4.23, s, 1 H;4.62, dd, 2H, J=9.98 Hz; 4.67, s, 1 H; 4.81, d, 1 H, J=3.8 Hz; 4.98, s,1 H; 5.08, d, 1 H, H₁₆ or H_(16′), ²J_(H16-H16′)=18.0 Hz; 6.08, t, 1 H,H₅, ³J_(H4-H5)=4.9 Hz; 6.76-6.85, m, 1 H; 6.95-7.29, m, 30H, H_(Ph).

Mass spectrometry: (MALDI+):

M+Na=965.4

M+K=981.3

Synthesis of the compound 17 (FIG. 21):

The first diastereoisomer of(2-{benzyl-[2,2-difluoro-2-(3(R),4(S)-tris-benzyloxy-6(R)-benzyloxy-methyl-2(R)-hydroxytetrahydro-pyran-2-yl)-acetyl)-amino}-2-phenylacetylamino)-aceticacid ethyl ester 16a (0.139 g; 0.147 mmol) is placed in a 25 mL flaskwith 6.6 mL of methanol and a dash of 10% palladium on charcoal (Pd/C)from a spatula. After having applied vacuum, a hydrogen balloon is setup and stirring is maintained overnight at room temperature.

The solution is filtered on celite, then evaporated in order to obtainproduct 17 as white crystals.

NMR data:

−¹⁹F-NMR (CD₃OD)

−108.37 (d, ²J_(F-F)=261.7 Hz); −109.29 (d, ²J_(F-F)=256.8 Hz), −111.04(d, ²J_(F-F)=261.7 Hz); −115.44 (d, ²J_(F-F)=256.8 Hz); −120.50, s.

¹H-NMR (CD₃OD)

1.19, t, 3H, H₁, ³J_(H1-H2)=7.1 Hz; 3.39-3.52, m, 1 H; 3.59-3.98, m, 7H;4.044.19, m, 2H; 4.28, dd, 1 H, ²J=17.7 Hz; 5.22, dd, 1 H, H₁₆, H₁₆,²J_(H16-H16′)=17.7 Hz; 5.67, s, 1 H, H₇; 6.69-7.40, m, 10H, H_(Ph).

Mass spectrometry: (direct introduction, FAB+):

M+Na=605.0

In the glucose series, preparation of the amide 21 is described (FIG.22).

In a 50 mL flask under argon, ester 6 (0.193 g, 0.291 mmol, 1 eq.) isdissolved in anhydrous dichloromethane (5 mL). Para-methoxybenzylamine22 (0.057 mL, 0.436 mmol, 1.5 eq.) is added and the mixture is leftunder stirring overnight. The solution is then evaporated in vacuo.

Purification is achieved by chromatography on a silica column with acyclohexane/ethyl acetate as eluent in proportions of nine for one.

After concentration, product 21 exists as a white solid with a 56% yieldby weight.

Analyses carried out for confirming the structure of the obtainedproduct 21 are shown below:

TLC

Rf=0.52, eluent: ethyl acetate/cyclohexane (3:7).

NMR data:

¹⁹F-NMR (282 MHz; solvent: deuterated chloroform (CDCl₃)): −117.38, d,J_(F-F)=257 Hz; −121.90, d, J_(F-F)=257 Hz

¹H-NMR (300 MHz; solvent: deuterated chloroform (CDCl₃))

3.3-5, m, 16H (cycle+4xOBn); 3.66, s, 3H: CH₃ (OMe); 6.73, d, J=8.4 Hz,2H: 2CH (PMB); 7.07, d, J=8.4 Hz, 2H: 2CH (PMB); 7.14-7.24, m, 20H: 4x5CH (Ph).

¹³C-NMR (75.5 MHz; solvent: deuterated chloroform (CDCl₃)):

43.35, CH₂(PMB); 55.68, CH₃(OMe), 68.68, CH₂(C6); 73.06, CH; 73.82,75.47, 75.67, 76.37: 4xCH₂(OBn); 77.83, CH; 78.62, CH; 83.79, CH; 96.59,dd, J_(C-F)=28.17 Hz and J_(C-F)=26.44 Hz, —CF₂CH(OH)O—; 112.79, dd,J_(C-F)=263.6 Hz and J_(C-F)=259.6 Hz, CF₂; 114.60, 2 CH(PMB); 137-138CH(Ph+PMB); 159.71, C quat. (C-OMe PBM);

163.32, dd, J_(C-F)=31.6 Hz and J_(C-F)=31.0 Hz, CF₂CONH.

-   Reduction of the ester function

By transforming the ester function of difluoroacetylated C-glycosidesinto other functions, a wide range of glycoconjugates may be accessed.The reactivity of this α ester function of a difluoromethylene group andnotably its reduction were investigated.

The ester function of compounds 2 (or 6) is reduced to an alcoholfunction by sodium tetraborohydride (NaBH4) or lithium aluminiumtetrahydride (LiAlH₄) in order to obtain compound 23 (FIG. 22). Thealcohol function of this compound is then oxidized into an aldehydefunction in order to obtain compound 24 by different methods such asSwern's, Dess-Martin's methods . . .

It should be noted that direct reduction of the alcohol into an aldehydeby diisobutylaluminium hydride (DIBAH) is possible on non-osidiccompounds.

-   Reduction of an ester 25 into an alcohol 26 (FIG. 23).

The ester 25 (30 mg; 45 nmol; 1 eq.), sodium tetraborohydride NaBH₄ (5mg; 134 nmol; 3 eq.) and 5 mL of ethanol (EtOH) are placed in 25 mLflask.

The solution is left under stirring at room temperature overnight andthen dry evaporated in vacuo.

The white precipitate is redissolved in 10 ml of water and 10 ml ofdichloromethane.

The phases are separated, the aqueous phase is extracted withdichloromethane (2×10 mL) and the organic phases are collected, dried onanhydrous magnesium sulphate and evaporated in vacuo to afford 24 mg ofthe alcohol 26 (38 nmol) with a 86% yield by weight.

Analyses carried out for confirming the structure of the obtainedproduct 26 are shown below:

TLC

Rf=0.44, eluent: ethyl acetate/cyclohexane (8:2).

NMR data:

¹⁹F-NMR (282 MHz, solvent: deuterated chloroform (CDCl₃))

−110.68, dm, ²J_(F-F)=259.7 Hz, J_(F-H) not measurable; −117.8, dm,²J_(F-F)=259.7 Hz, J_(F-H) not measurable

¹H-NMR (300 MHz, solvent: deuterated chloroform (CDCl₃))

0.00, s, 6H (2x CH₃ TBDMS); 0.84, s, 9H (3x CH₃ TBDMS);. 3.39-4.96, m,15H; 7.23-7.33, m, 15H (3x 5CH Ph)

¹³C-NMR (75.5 MHz, solvent: deuterated chloroform (CDCl₃))-DEPT 135-5.04and −5.09, 2CH₃(TBDMS), 26.25, 3 CH₃(TBDMS); 62.37, CH₂(C6); 64.16, CH₂,t, ²J_(C-F)=31 Hz (CF₂CH₂OH); 73.23 , 74.87 et 75.64, 3x CH₂ (OBn);73.45, 74.80 , 79.52 and 84.81, 4x CH (C2 à C5); 78.15, CH, dd,²J_(C-F)=26 and 29 Hz; 128.1-128.9, 3x 5 CH (OBn).

1. A gem-difluorinated compound of formula:

wherein R¹ is a group comprising an alkyl chain substituted with atleast one amine, amide, or acid function, R² is a hydrogen atom H or afree or protected alcohol function, R³ is notably an H, CH₃, CH₂OH,CH₂-OGP group wherein GP is a protective group such as an alkyl, benzyl(Bn), trimethylsilyl (TMS), tert-butyl-dimethylsilyl (TBDMS),tert-butyldiphenylsilyl (TBDPS), acetate (Ac) . . . , Y, Y′, Y″ areindependent groups wherein Y, Y′, Y″=H, OR, N₃, NR′R″, SR′″ . . . withR=H, Bn, Ac, TMS, TBDMS, TBDPS, . . . , R′, R″=H, alkyl, allyl, Bn,tosylate (Ts), C(=O)—alkyl, C(═O)-Bn, . . . , R′″=H, alkyl, Ac.
 2. Thecompound according to claim 1, comprising a C-glycoside of generalformula:

wherein R⁵ and R⁶=H or a group either functionalized or not such as afunctionalized carbon chain bearing i.a. an amine, amino acid,aminoester function, a peptide chain, a protein, a carbohydrate, asteroid, or a triterpene, an alkaloid, a lignane, or compounds ofpharmacological interest.
 3. The compound according to claim 1,comprising a glycoconjugated compound of general formula:

wherein R⁵, R⁶, R⁷ and R⁹=H or a group either functionalized or not,such as a functionalized carbon chain bearing i.a. an amine, amino acid,aminoester function, a peptide chain, a protein, a carbohydrate, asteroid, or a triterpene, an alkaloid, a lignane, or compounds ofpharmacological interest.
 4. A method for preparing a gem-difluorinatedcompound of formula:

wherein R¹ is a group comprising an alkyl chain substituted with atleast one amine, or amide function, R² is a hydrogen atom H or a free orprotected alcohol function, R³ is notably an H, CH₃, CH₂OH, CH₂-OGPgroup wherein GP is a protective group such as an alkyl, benzyl (Bn),trimethylsilyl (TMS), tert-butyl-dimethylsilyl (TBDMS),tert-butyldiphenylsilyl (TBDPS), acetate (Ac) . . . , Y, Y′, Y″ areindependent groups wherein Y, Y′, Y″=H, OR, N₃, NR′R″, SR′″ . . . withR=H, Bn, Ac, TMS, TBDMS, TBDPS, . . . , R′, R″=H, alkyl, allyl, Bn,tosylate (Ts), C(=O)-alkyl, C(=O)-Bn, . . . , R′″=H, alkyl, Ac, saidmethod comprising a reaction between a lactone and a halogenatedderivative of general formula XCF₂CO₂R⁸, wherein X is a halogen, in thepresence of zinc, or of a lanthanide derivative and R⁸=alkyl, aryl . . .5. The method according to claim 4, wherein said lanthanide derivativeis samarium diiodide.
 6. The method according to claim 4, wherein saidsugar derivative is obtained in one or more steps from a correspondingcommercially available sugar.
 7. The method according to claim 4,wherein said reaction is followed by a deoxygenation.
 8. The methodaccording to claim 4, wherein the R⁸ group comprises an ester functionwhich is reduced to alcohol.
 9. The method according to claim 4, whereinthe R⁸ group comprises an ester function which is either reduced toalcohol then oxidized into an aldehyde or hemiacetal, or directlyreduced into aldehyde.
 10. A method for preparing a gem-difluorinatedcompound of formula:

wherein R¹=C(=O)—NR⁵R⁶, wherein R⁵ and R⁶=H or a group eitherfunctionalized or not, such as a functionalized carbon chain bearingi.a. an amine, amino acid, aminoester function, a peptide chain, aprotein, a carbohydrate, a steroid, or a triterpene, an alkaloid, alignane, or compounds of pharmacological interest, R² is a hydrogen atomH or a free or protected alcohol function, R³ is an H, CH₃, CH₂OH,CH₂-OGP group wherein GP is a protective group such as an alkyl, benzyl(Bn), trimethylsilyl (TMS), tert-butyl-dimethylsilyl (TBDMS),tert-butyldiphenylsilyl (TBDPS), acetate (Ac) . . . , Y, Y′, Y″ areindependent groups wherein Y, Y′, Y″=H, OR, N₃, NR′R″, SR′″ . . . withR=H, Bn, Ac, TMS, TBDMS, TBDPS, . . . , R′, R″=H, alkyl, allyl, Bn,tosylate (Ts), C(=O)-alkyl, C(=O)-Bn, . . . , R′″=H, alkyl, Ac, saidmethod comprising a Ugi reaction with an amine, an aldehyde and anisonitrile.
 11. A method for preparing a gem-difluorinated compound offormula:

wherein R¹=—C(=O)-NR⁵R⁶, wherein R⁵ and R⁶=H or a group eitherfunctionalized or not, such as a functionalized carbon chain bearingi.a. an amine, amino acid, aminoester function, a peptide chain, aprotein, a carbohydrate, a steroid, or a triterpene, an alkaloid, alignane, or compounds of pharmacological interest, R² is a hydrogen atomH or a free or protected alcohol function, R³ is an H, CH₃, CH₂OH,CH₂-OGP group wherein GP is a protective group such as an alkyl, benzyl(Bn), trimethylsilyl (TMS), tert-butyl-dimethylsilyl (TBDMS),tert-butyldiphenylsilyl (TBDPS), acetate (Ac) . . . , Y, Y′, Y″ areindependent groups wherein Y, Y′, Y″=H, OR, N₃, NR′R″, SR′″ . . . withR=H, Bn, Ac, TMS, TBDMS, TBDPS, . . . , R′, R″=H, alkyl, allyl, Bn,tosylate (Ts), C(=O)-alkyl, C(=O)-Bn, . . . , R′″=H, alkyl, Ac, saidmethod comprising a coupling reaction of a sugar derivative with anamine.
 12. A composition, comprising at least one compound according toclaim 1 or one of its derivatives or one of its salts obtained byaddition to a pharmaceutically acceptable organic or mineral acid. 13.The use of a gem-difluorinated compound according to claim 1, forpreparing antitumoral drugs.
 14. The use of a gem-difluorinated compoundaccording to claim 1, for preparing antiviral drugs.
 15. The use of agem-difluorinated compound according to claim 1, for preparinghypoglycemic drugs.
 16. The use of a gem-difluorinated compoundaccording to claim 1, for preparing compounds for immunology.
 17. Theuse of a gem-difluorinated compound according to claim 1, for preparinganti-inflammatory compounds.
 18. The use of a gem-difluorinated compoundaccording to claim 1, for preparing compounds for cosmetology.
 19. Theuse of a gem-difluorinated compound according to claim 1, for preparingglycopeptide analogs of antifreeze molecules.